Olopatadine hydrochloride, chemical name dibenz[b,e]oxepin-2-acetic acid, 11-[3-(dimethylamino)propylidene]-6,11-dihydro hydrochloride, (11Z), of formula (I)
is a novel antihistamine marketed by Kyowa Hakko under the name of Allelock®. In particular, olopatadine is selective for histamine H1 receptors, predominantly localised in the bronchi, the cardiovascular system, the central nervous system and the intestine. As a formulation for oral administration, it is used in the oral treatment of the symptoms of allergic rhinitis, urticaria and dermatitis.
Both ophthalmic (Patanol®) (Pataday® or Patanol Plus®) and nasal spray (Patanase®) formulations are known.
On the other hand, its use as an anti-asthmatic is still in phase-II clinical development.
Olopatadine has first been described by GlaxoSmithKline (EP 214779) and subsequently by Kyowa (EP 235796), while its use in the treatment of conjunctivitis has been described by Alcon and Kyowa (EP 799044).
Regarding its preparation, the synthetic processes described in the product patent use isoxepac (or dibenz[b,e]oxepin-2-acetic acid, 6,11-dihydro-1′-oxo) as an advanced intermediate.
However, the known processes for the preparation of olopatadine consisting of the preparation of isoxepac have the drawback of giving a limited yield of final product. In addition, the product obtained is unsatisfactory in terms of purity, thus making the process for the attainment of a pharmaceutically acceptable active substance longer, more complex and more costly.
The originator states in the Journal of Medicinal Chemistry, 1992, 35, pages 2074-2084 that the attempts to prepare Olopatadine esters and analogs (compounds 37-40) employing the same Wittig reaction conditions employed starting from Isoxepac, but starting from Isoxepac esters and analogs, resulted in the recovery of the starting materials that means no reaction between the substrates.